The present invention provides method and apparatus for accomplishing mass transfer of a dissolved component from a first fluid phase to another, second fluid phase immiscible with the first phase (e.g. by liquid-liquid extraction or gas absorption) using microporous hollow-fiber membranes. This invention is especially useful for the purpose of preparation of analytical samples for subsequent assay by instrumental methods, including methods employing antibodies or antigens.. It has been found that the present invention provides improved and more convenient analytical sample preparation by mass transfer purification (e.g. liquid extraction or gas absorption) of an analyte and overcomes a number of problems of the prior art. The invention, although generally applicable to using mass transfer between fluid phases for analytical sample preparation, will be described mainly in terms of liquid-liquid extraction.
Liquid-liquid extraction (herein sometimes referred to as LLE) is a general and widely used method of preparing samples for later assay by liquid chromatography, gas chromatography, spectrophotometry and other analytical instrumental methods. LLE is particularly useful when the compound to be assayed is lipophilic as in the case of a fat soluble drug. In such a case, the solute (i.e. the drug) would be extracted from the analyte (e.g., a serum or urine sample) into a liquid solvent (often an organic or hydrocarbon solvent). It could then be back-extracted (or stripped) from the solvent into another liquid, often aqueous and referred to herein as the stripping phase, the product liquid or the product phase. LLE helps to free the soute (e.g. a drug) from interfering substances and can concentrate the solute as well. During forward extraction LLE will tend to concentrate a solute compound in an organic solvent liquid, if the compound is more soluble in the organic solvent liquid than in an aqueous analyte sample. The equilibrium condition of two immiscible phases in contact is often expressed in terms of a distribution coefficient, D, herein defined as:
______________________________________ D = (equilibrium concentration of solute (1) in organic solvent phase)/(equilibrium concentration of solute in aqueous phase) ______________________________________
A value of D greater than unity states that the organic phase is favored over the aqueous phase by the solute of interest. A "forward" extraction of a solute from an aqueous feed liquid phase to an organic solvent liquid phase is favored by a distribution coefficient greater than unity as defined by the foregoing equation (1). Back extraction or stripping of a compound from organic solvent liquid to aqueous stripping liquid is favored by a distribution coefficient smaller than unity as defined by the foregoing equation. It is often possible to adjust the distribution coefficient to a favorable value by choosing suitable conditions of pH, temperature and other conditions.
For ease of notation and uniformity, the analyte or liquid sample-to-be-analyzed will often be referred to herein as the feed, feed liquid, feed sample or feed phase, the solvent as solvent liquid or solvent phase (the solvent liquid will often be a hydrocarbon or organic solvent, including organic solvents containing reverse micelles) and the stripping liquid as product, product phase, product liquid or stripping phase. The use of LLE for preparation of analytical samples is further discussed in the following references: D. N. Bailey and M. Kleiner, J. Anal. Toxicology, 8, 26 (1984): E. H. Forester and M. F. Mason, J. Foren. Sci, 19, 155 (1974); I. Sunshine (ed), Handbook of Analytical Toxicology, CRC Press, Cleveland (1969).
In addition to being a traditional method of analytical sample preparation, LLE is also a unit operation of chemical engineering used for stage-wise and continuous operations on a larger scale. The smaller-scale use of LLE for analytical sample preparation is generally a batch process, whereas the traditional use of LLE as a larger-scale unit operation is generally a continuous-flow operation. The latter use of LLE is described generally in McCabe, W. L. and Smith, J. C., Unit Operations of Chemical Engineering, 3rd Ed., McGraw-Hill, N.Y., 1976, pp. 465-800.
Traditional LLE applied to analytical sample preparation requires the handling of several different liquids, is labor intensive requiring considerable manual manipulation, employs considerable volumes of solvents that are often toxic and suffers from problems such as formation of emulsions which are slow and difficult to separate. For such reasons a new approach has gained favor in recent years in which an organic solvent phase is bonded to a solid support such as silica. This modern innovation is often called solid phase extraction or SPE. SPE is described further by the following references: Tibbins, B.: Nature, 334, pp. 273-274, 21 Jul. 1988; Amer. Biotech. Lab, 5, (1), pp. 25-31 (1987); Amer. Labor News, p. 8, June, 1987; Majors, R. E., LC-GC, 4 (10), pp. 972-9844 (1986); McDowell, R. D., et al: J. Pharm. Biomed. Anal., 4 (1), pp. 3-21 (1986).